Research interests: Genetic mechanism underlying mitochondrial pathology, neurodegeneration, and muscle loss using Drosophila as a model organism.
Honors & Awards
Young Investigator Award, Korean Drosophila Research Society (2019)
Invited speaker at the 73rd annual conference, The Korean Association of Biological Sciences (2018)
Global scholarship award for foreign graduate students, Kookmin University (2016)
PhD, Kookmin University, Molecular Genetics (2019)
MS, Tribhuvan University, Medical Microbiology (2013)
BS, Tribhuvan University, Microbiology (2010)
Bingwei Lu, Postdoctoral Faculty Sponsor
Regulation of reverse electron transfer at mitochondrial complex I by unconventional Notch action in cancer stem cells.
1800; 57 (2): 260
Metabolic flexibility is a hallmark of many cancers where mitochondrial respiration is critically involved, but the molecular underpinning of mitochondrial control of cancer metabolic reprogramming is poorly understood. Here, we show that reverse electron transfer (RET) through respiratory chain complex I (RC-I) is particularly active in brain cancer stem cells (CSCs). Although RET generates ROS, NAD+/NADH ratio turns out to be key in mediating RET effect on CSC proliferation, in part through the NAD+-dependent Sirtuin. Mechanistically, Notch acts in an unconventional manner to regulate RET by interacting with specific RC-I proteins containing electron-transporting Fe-S clusters and NAD(H)-binding sites. Genetic and pharmacological interference of Notch-mediated RET inhibited CSC growth in Drosophila brain tumor and mouse glioblastoma multiforme (GBM) models. Our results identify Notch as a regulator of RET and RET-induced NAD+/NADH balance, a critical mechanism of metabolic reprogramming and a metabolic vulnerability of cancer that may be exploited for therapeutic purposes.
View details for DOI 10.1016/j.devcel.2021.12.020
View details for PubMedID 35077680
Inefficient quality control of ribosome stalling during APP synthesis generates CAT-tailed species that precipitate hallmarks of Alzheimer's disease.
Acta neuropathologica communications
2021; 9 (1): 169
Amyloid precursor protein (APP) metabolism is central to Alzheimer's disease (AD) pathogenesis, but the key etiological driver remains elusive. Recent failures of clinical trials targeting amyloid-beta (Abeta) peptides, the proteolytic fragments of amyloid precursor protein (APP) that are the main component of amyloid plaques, suggest that the proteostasis-disrupting, key pathogenic species remain to be identified. Previous studies suggest that APP C-terminal fragment (APP.C99) can cause disease in an Abeta-independent manner. The mechanism of APP.C99 pathogenesis is incompletely understood. We used Drosophila models expressing APP.C99 with the native ER-targeting signal of human APP, expressingfull-length human APP only, or co-expressing full-length human APP and beta-secretase (BACE), to investigate mechanisms of APP.C99 pathogenesis. Key findings are validated in mammalian cell culture models, mouse 5xFAD model, and postmortem AD patient brain materials. We find that ribosomes stall at the ER membrane during co-translational translocation of APP.C99, activating ribosome-associated quality control (RQC) to resolve ribosome collision andstalled translation. StalledAPP.C99 species with C-terminal extensions (CAT-tails) resulting from inadequate RQC are prone to aggregation, causing endolysosomal and autophagy defects and seeding the aggregation of amyloid beta peptides, the main component of amyloid plaques. Genetically removing stalled and CAT-tailed APP.C99 rescued proteostasis failure, endolysosomal/autophagy dysfunction, neuromuscular degeneration, and cognitive deficits in AD models. Our findingofRQC factor deposition at the core of amyloid plaques from AD brains further supports the central role of defective RQC of ribosome collision andstalled translation in AD pathogenesis. These findings demonstrate that amyloid plaque formation is the consequence and manifestation of a deeper level proteostasis failure caused by inadequate RQC of translationalstallingand the resultantaberrantly modified APP.C99 species, previously unrecognized etiological drivers of ADandnewly discovered therapeutic targets.
View details for DOI 10.1186/s40478-021-01268-6
View details for PubMedID 34663454
Cucurbitacin B Activates Bitter-Sensing Gustatory Receptor Neurons via Gustatory Receptor 33a in Drosophila melanogaster.
Molecules and cells
2020; 43 (6): 530-538
The Gustatory system enables animals to detect toxic bitter chemicals, which is critical for insects to survive food induced toxicity. Cucurbitacin is widely present in plants such as cucumber and gourds that acts as an anti-herbivore chemical and an insecticide. Cucurbitacin has a harmful effect on insect larvae as well. Although various beneficial effects of cucurbitacin such as alleviating hyperglycemia have also been documented, it is not clear what kinds of molecular sensors are required to detect cucurbitacin in nature. Cucurbitacin B, a major bitter component of bitter melon, was applied to induce action potentials from sensilla of a mouth part of the fly, labellum. Here we identify that only Gr33a is required for activating bitter-sensing gustatory receptor neurons by cucurbitacin B among available 26 Grs, 23 Irs, 11 Trp mutants, and 26 Gr-RNAi lines. We further investigated the difference between control and Gr33a mutant by analyzing binary food choice assay. We also measured toxic effect of Cucurbitacin B over 0.01 mM range. Our findings uncover the molecular sensor of cucurbitacin B in Drosophila melanogaster. We propose that the discarded shell of Cucurbitaceae can be developed to make a new insecticide.
View details for DOI 10.14348/molcells.2020.0019
View details for PubMedID 32451368
Molecular sensor of nicotine in taste of Drosophila melanogaster
INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY
2019; 111: 103178
Nicotine is an alkaloid and potent parasympathomimetic stimulant found in the leaves of many plants including Nicotiana tabacum, which functions as an anti-herbivore chemical and an insecticide. Chemoreceptors embedded in the gustatory receptor neurons (GRNs) enable animals to judge the quality of bitter compounds and respond to them. Various taste receptors such as gustatory receptors (GRs), ionotropic receptors (IRs), transient receptor potential channels (TRPs), and pickpocket channels (PPKs) have been shown to have important roles in taste sensation. However, the mechanism underlying nicotine taste sensation has not been resolved in the insect model. Here we identify molecular receptors to detect the taste of nicotine and provide electrophysiological and behavioral evidence that gustatory receptors are required for avoiding nicotine-laced foods. Our results demonstrate that gustatory receptors are reasonable targets to develop new pesticides that maximize the insecticidal effects of nicotine.
View details for DOI 10.1016/j.ibmb.2019.103178
View details for Web of Science ID 000478706500007
View details for PubMedID 31226410
Mechanism of Acetic Acid Gustatory Repulsion in Drosophila
2019; 26 (6): 1432-+
The decision to consume or reject a food based on the degree of acidity is critical for animal survival. However, the gustatory receptors that detect sour compounds and influence feeding behavior have been elusive. Here, using the fly, Drosophila melanogaster, we reveal that a member of the ionotropic receptor family, IR7a, is essential for rejecting foods laced with high levels of acetic acid. IR7a is dispensable for repulsion of other acidic compounds, indicating that the gustatory sensation of acids occurs through a repertoire rather than a single receptor. The fly's main taste organ, the labellum, is decorated with bristles that house dendrites of gustatory receptor neurons (GRNs). IR7a is expressed in a subset of bitter GRNs rather than GRNs dedicated to sour taste. Our findings indicate that flies taste acids through a repertoire of receptors, enabling them to discriminate foods on the basis of acid composition rather than just pH.
View details for DOI 10.1016/j.celrep.2019.01.042
View details for Web of Science ID 000457709200007
View details for PubMedID 30726729
View details for PubMedCentralID PMC6490183
Gustatory receptor 28b is necessary for avoiding saponin in Drosophila melanogaster
2019; 20 (2)
Saponins function as a natural self-defense mechanism for plants to deter various insects due to their unpleasant taste and their toxicity. Here, we provide evidence that saponin from Quillaja saponaria functions as an antifeedant as well as an insecticide to ward off insects in both the larval and the adult stages. Using a behavioral screen of 26 mutant fly lines, we show that the Gr28b gene cluster plays a role in saponin avoidance in the labellum. The Gr28b mutant does not avoid saponin and exhibits increased lethality when fed saponin-mixed food. Tissue-specific rescue experiments with five different Gr28b isoforms revealed that only the Gr28b.c isoform is required for saponin sensation. We propose that in contrast to sensing many other bitter compounds, saponin sensing does not require the function of core taste receptors, such as GR32a, GR33a, and GR66a. Our results reveal a novel role for GR28b in taste. In addition, the ability of saponin to act as insecticides as well as antifeedants suggests its potential application in controlling insect pests.
View details for DOI 10.15252/embr.201847328
View details for Web of Science ID 000459026000012
View details for PubMedID 30622216
View details for PubMedCentralID PMC6362386
The multidimensional ionotropic receptors of Drosophila melanogaster
INSECT MOLECULAR BIOLOGY
2018; 27 (1): 1–7
Ionotropic receptors (IRs), which form ion channels, can be categorized into conserved 'antennal IRs', which define the first olfactory receptor family of insects, and species-specific 'divergent IRs', which are expressed in gustatory receptor neurones. These receptors are located primarily in cell bodies and dendrites, and are highly enriched in the tips of the dendritic terminals that convey sensory information to higher brain centres. Antennal IRs play important roles in odour and thermosensation, whereas divergent IRs are involved in other important biological processes such as taste sensation. Some IRs are known to play specific biological roles in the perception of various molecules; however, many of their functions have not yet been defined. Although progress has been made in this field, many functions and mechanisms of these receptors remain unknown. In this review, we provide a comprehensive summary of the current state of knowledge in this field.
View details for DOI 10.1111/imb.12347
View details for Web of Science ID 000419247300001
View details for PubMedID 28857341